Project description:Globally, asthma is a chronic inflammatory respiratory disease affecting over 300 million people. Some asthma patients remain poorly controlled by conventional therapies and experience more life-threatening exacerbations. Vitamin D, as an adjunct therapy, may improve disease control in severe asthma patients since vitamin D enhances glucocorticoid responsiveness and mitigates airway smooth muscle (ASM) hyperplasia. We sought to characterize differences in transcriptome responsiveness to vitamin D between fatal asthma- and non-asthma-derived ASM by using RNA-Seq to measure ASM transcript expression in five donors with fatal asthma and ten non-asthma-derived donors at baseline and with vitamin D treatment. Based on a Benjamini-Hochberg corrected p-value <0.05, 838 genes were differentially expressed in fatal asthma vs. non-asthma-derived ASM at baseline, and vitamin D treatment compared to baseline conditions induced differential expression of 711 and 867 genes in fatal asthma- and non-asthma-derived ASM, respectively. Functional gene categories that were highly represented in all groups included extracellular matrix, and responses to steroid hormone stimuli and wounding. Genes differentially expressed by vitamin D also included cytokine and chemokine activity categories. Follow-up qPCR and individual analyte ELISA experiments were conducted for four cytokines (i.e. CCL2, CCL13, CXCL12, IL8) to measure TNFα-induced changes by asthma status and vitamin D treatment. Vitamin D inhibited TNFα-induced IL8 protein secretion levels to a comparable degree in fatal asthma- and non-asthma-derived ASM even though IL8 had significantly higher baseline levels in fatal asthma-derived ASM. Our findings identify vitamin D-specific gene targets and provide transcriptomic data to explore differences in the ASM of fatal asthma- and non-asthma-derived donors.

| S-EPMC4514847 | biostudies-literature

Fatal Asthma and Non-Asthma Donor-Derived Airway Smooth Muscle Transcriptome Response to Glucocorticoid Treatment

Project description:Asthma is a chronic inflammatory respiratory disease affecting over 300 million people around the world. Some asthma patients remain poorly controlled by conventional therapies and experience more life-threatening exacerbations. While patients with severe, refractory disease represent a heterogeneous group, a feature shared by most includes glucocorticoid insensitivity. We sought to characterize differences in the airway smooth muscle transcriptome response to glucocorticoids in fatal asthma vs. non-asthma donors. RNA-Seq was used to measure airway smooth muscle transcript expression differences between 9 donors with fatal asthma and 8 non-asthma donors. Cells from each donor were treated with budesonide or with vehicle control. Poly(A)-selected RNA-Seq libraries were prepared with the Illumina TruSeq method. An Illumina HiSeq 2500 instrument was used to generate 125 base pair paired-end reads.

2018-12-31 | GSE94335 | GEO

Why Is ORMDL3 on Chromosome 17q21 Highly Linked to Asthma?

Project description: Not available

| S-EPMC6376625 | biostudies-literature

Asthma 17q21 polymorphism associates with decreased risk of COVID-19 in children.

Project description: Not available

| S-EPMC9538222 | biostudies-literature

Fatal Asthma vs. Control Human Airway Smooth Muscle Transcriptome Changes in Response to Vitamin D or Albuterol

Project description:Rationale: Asthma is a chronic inflammatory airway disease. Children with severe asthma have lower levels of vitamin D than children with moderate asthma, and among children with severe asthma, airway smooth muscle (ASM) mass is inversely related to vitamin D levels. Beta2 agonists are a common asthma medication that act partly by targetting the ASM. We used RNA-Seq to characterize the human ASM transcriptome of fatal and asthma vs. contols at baseline and under two treatment conditions. Methods: The Illumina TruSeq assay was used to prepare 75bp paired-end libraries for ASM cells from white donors, 6 with fatal asthma and 12 control donors under three treatment conditions: 1) no treatment; 2) treatment with a β2-agonist (i.e. Albuterol, 1μM for 18h); 3) treatment with vitamin D 100 nM for 18h). Llibraries were sequenced with an Illumina Hi-Seq 2000 instrument. The Tuxedo Suite Tools were used to align reads to the hg19 reference genome, assemble transcripts, and perform differential expression analysis using the protocol described in https://github.com/blancahimes/taffeta

2014-12-01 | GSE58434 | GEO

Does reduced zona pellucida binding protein 2 (ZPBP2) expression on chromosome 17q21 protect against asthma?

Project description: Not available

| S-EPMC6078789 | biostudies-literature

Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia.

Project description:Genome-wide association studies followed by replication provide a powerful approach to map genetic risk factors for asthma. We sought to search for new variants associated with asthma and attempt to replicate the association with four loci reported previously (ORMDL3, PDE4D, DENND1B and IL1RL1). Genome-wide association analyses of individual single nucleotide polymorphisms (SNPs), rare copy number variants (CNVs) and overall CNV burden were carried out in 986 asthma cases and 1846 asthma-free controls from Australia. The most-associated locus in the SNP analysis was ORMDL3 (rs6503525, P = 4.8 × 10⁻⁷). Five other loci were associated with P < 10⁻⁵, most notably the chemokine CXC motif ligand 14 (CXCL14) gene (rs31263, P = 7.8 × 10⁻⁶). We found no evidence for association with the specific risk variants reported recently for PDE4D, DENND1B and ILR1L1. However, a variant in IL1RL1 that is in low linkage disequilibrium with that reported previously was associated with asthma risk after accounting for all variants tested (rs10197862, gene wide P = 0.01). This association replicated convincingly in an independent cohort (P = 2.4 × 10⁻⁴). A 300-kb deletion on chromosome 17q21 was associated with asthma risk, but this did not reach experiment-wide significance. Asthma cases and controls had comparable CNV rates, length and number of genes affected by deletions or duplications. In conclusion, we confirm the association between asthma risk and variants in ORMDL3 and identify a novel risk variant in IL1RL1. Follow-up of the 17q21 deletion in larger cohorts is warranted.

| S-EPMC3060316 | biostudies-literature

Association of genetic variants in chromosome 17q21 and adult-onset asthma in a Chinese Han population.

Project description:BackgroundGenome-wide association studies of asthma have identified a novel region containing ORMDL3 at chromosome 17q21 that is strongly associated with childhood-onset asthma and significantly linked to ORMDL3 transcript abundance. These results have been successfully replicated in childhood-onset asthma cohorts in several ethnic groups. In this study, we aimed to evaluate the association of polymorphisms in ORMDL3, GSDMB, ZPBP2 and IKZF3 and adult-onset asthma in a Chinese Han population.MethodsWe genotyped 5 single nucleotide polymorphisms (SNPs) at chromosome 17q21 in 1,366 Han Chinese people comprising 710 patients with adult-onset asthma and 656 healthy controls. We compared the 2 groups in terms of allele and haplotype frequencies. Transcript levels were measured in leukocytes from 61 asthma patients by quantitative real-time PCR.ResultsWe found the 5 SNPs significantly associated with asthma (P<0.05), of which 2, rs11557467 and rs9303277, were strongly associated (P<0.001). Subjects carrying the G allele of rs11557467 or the C allele of rs9303277 showed increased risk of asthma (odds ratio [OR] 1.27, 95% confidence interval 1.07-1.51, P = 0.006, and OR 1.27, 1.07-1.49, P = 0.005, respectively), even after adjusting for age and sex. The risk of asthma was lower for carriers of the haplotype CTGTT (OR 0.81, 0.67-0.97, P = 0.02). The risk allele for each SNP was associated with increased expression of ORMDL3 and GSDMB in leukocytes (all p<0.05).ConclusionsOur replication study suggests that variants in 17q21 are significantly associated with risk of adult-onset asthma and gene expression in a Chinese Han population.

| S-EPMC3207945 | biostudies-literature

Airway smooth muscle in the pathophysiology and treatment of asthma.

Project description:Airway smooth muscle (ASM) plays an integral part in the pathophysiology of asthma. It is responsible for acute bronchoconstriction, which is potentiated by constrictor hyperresponsiveness, impaired relaxation and length adaptation. ASM also contributes to airway remodeling and inflammation in asthma. In light of this, ASM is an important target in the treatment of asthma.

| S-EPMC3633438 | biostudies-literature

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